Real-time positron emission tomography for range verification of particle radiotherapy

Owing to the superior ability to deliver the prescribed radiation dose to cancer tissue with a reduced dose to surrounding healthy tissues, there has been a sustained increase in cancer radiotherapy with charged particles, such as protons, helium and carbon ions. Achieving such superior dose delivery is, however, nontrivial as the dose distribution by charged particles is sensitive to uncertainties in range prediction, patient setup errors and changes in patient anatomy. This thesis investigates a technique to provide feedback on the particle range, based on the imaging of photons, emitted via the radioactive decay of positron emitting nuclides produced through nuclear reactions. Retrieving such feedback on a short time scale provides a trigger for corrective actions such as online treatment adaptation. Experiments on the production of short-lived positron emitters during irradiation with helium ions as reported in chapter 3 and the PET imaging of these nuclides during irradiations with helium ions (chapter 4) and protons (chapter 5) were performed. It was observed that the short-lived positron emitter nitrogen-12 (half-life = 11 ms), previously observed during irradiation with protons, is also produced during irradiation of a tissue surrogate, PMMA, with helium ions. Extrapolating the experimental results to an optimized implementation of the method, feedback on the particle range at a time-scale of about 50 ms into an irradiation with 109 protons and 4.0 × 108 helium-4 ions with a precision (1σ) of 0.5 mm and 0.9 mm is predicted. The next steps towards clinical implementation are detailed in chapter 6

Real-Time PET Imaging for Range Verification of Helium Radiotherapy

Real-time range verification of particle beams is important for optimal exploitation of the tissue-sparing advantages of particle therapy. Positron Emission Tomography (PET) of the beam-induced positron emitters such as 15O (T1/2 = 122 s) and 11C (T1/2 = 1223 s) has been used for monitoring of therapy in both clinical and preclinical studies. However, the half-lives of these nuclides preclude prompt feedback, i.e., on a sub-second timescale, on dose delivery. The in vivo verification technique relying on the in-beam PET imaging of very short-lived positron emitters such as 12N (T1/2 = 11 ms), recently proposed and investigated in feasibility experiments with a proton beam, provides millimeter precision in range measurement a few tens of milliseconds after the start of an irradiation. With the increasing interest in helium therapy, it becomes relevant to study the feasibility of prompt feedback using PET also for helium beams. A recent study has demonstrated the production of very short-lived nuclides (T1/2 = 10 ms attributed to 12N and/or 13O) during irradiation of water and graphite with helium ions. This work is aimed at investigating the range verification potential of imaging these very short-lived nuclides. PMMA targets were irradiated with a 90 AMeV 4He pencil beam consisting of a series of pulses of 10 ms beam-on and 90 ms beam-off. Two modules of a modified Siemens Biograph mCT PET scanner (21 × 21 cm2), installed 25 cm apart, were used to image the beam-induced PET activity during the beam-off periods. For the irradiation of PMMA, we identify the very short-lived activity earlier observed to be 12N (T1/2 = 11.0 ms). The range precision determined from the 12N activity profile that is measured after just one beam pulse was found to be 9.0 and 4.1 mm (1σ) with 1.3 × 1074He ions per pulse and 6.6 × 1074He ions per pulse, respectively. When considering 4.0 × 1074He ions, which is about the intensity of the most intense distal layer spot in a helium therapy plan, a range verification precision in PMMA of 5.7 mm (1σ) can be realized. The range precision scales approximately with the inverse square root of the number of 4He ions, i.e., the relative statistical accuracy of the number of coincidence events. Thus, when summing data over about 10 distal layer spots, this study shows good prospects for obtaining 1.8 mm (1σ) precision in range verification, within 50 ms after the start of a helium irradiation by in-beam PET imaging (scanner 29% solid angle) of 12N

Author Correction: Proton range verification with MACACO II Compton camera enhanced by a neural network for event selection (vol 11, 23903, 2021)

The applicability extent of hadron therapy for tumor treatment is currently limited by the lack of reliable online monitoring techniques. An active topic of investigation is the research of monitoring systems based on the detection of secondary radiation produced during treatment. MACACO, a multi-layer Compton camera based on LaBr3 scintillator crystals and SiPMs, is being developed at IFIC-Valencia for this purpose. This work reports the results obtained from measurements of a 150 MeV proton beam impinging on a PMMA target. A neural network trained on Monte Carlo simulations is used for event selection, increasing the signal to background ratio before image reconstruction. Images of the measured prompt gamma distributions are reconstructed by means of a spectral reconstruction code, through which the 4.439 MeV spectral line is resolved. Images of the emission distribution at this energy are reconstructed, allowing calculation of the distal fall-off and identification of target displacements of 3 mm

The production of positron emitters with millisecond half-life during helium beam radiotherapy

Therapy with helium ions is currently receiving significantly increasing interest because helium ions have a sharper penumbra than protons and undergo less fragmentation than carbon ions and thus require less complicated dose calculations. For any ion of interest in hadron therapy, the accuracy of dose delivery is limited by range uncertainties. This has led to efforts by several groups to develop in vivo verification techniques, including positron emission tomography (PET), for monitoring of the dose delivery. Beam-on PET monitoring during proton therapy through the detection of short-lived positron emitters such as N-12 (T-1/2 = 11 ms), an emerging PET technique, provides an attractive option given the achievable range accuracy, minimal susceptibility to biological washout and provision of near prompt feedback. Extension of this approach to helium ions requires information on the production yield of relevant short-lived positron emitters. This study presents the first measurements of the production of short-lived positron emitters in water, graphite, calcium and phosphorus targets irradiated with 59 MeV/u He-3 and 50 MeV/u He-4 beams. For these targets, the most produced short-lived nuclides are O-13/N-12 (T-1/2 = 8.6/11 ms) on water, O-13/N-12 on graphite, Ti-43/Sc-41/Sc-42 (T-1/2 = 509-680 ms) on calcium, P-28 (T-1/2 = 268 ms) on phosphorus. A translation of the results from elemental targets to PMMA and representative tissues such as adipose tissue, muscle, compact and cortical bone, shows the dominance of O-13/N-12 in at least the first 20 s of an irradiation with He-4 and somewhat longer with He-3. As the production of O-13/N-12 in a He-3 irradiation is 3-4 times higher than in a He-4 irradiation, from a statistical point of view, range verification using O-13/N-12 PET imaging will be about 2 times more precise for a He-3 irradiation compared to a He-4 irradiation

Feasibility of quasi-prompt PET-based range verification in proton therapy

Compared to photon therapy, proton therapy allows a better conformation of the dose to the tumor volume with reduced radiation dose to co-irradiated tissues. In vivo verification techniques including positron emission tomography (PET) have been proposed as quality assurance tools to mitigate proton range uncertainties. Detection of differences between planned and actual dose delivery on a short timescale provides a fast trigger for corrective actions. Conventional PET-based imaging of 15O (T1/2 = 2 min) and 11C (T1/2 = 20 min) distributions precludes such immediate feedback. We here present a demonstration of near real-time range verification by means of PET imaging of 12N (T1/2 = 11 ms). PMMA and graphite targets were irradiated with a 150 MeV proton pencil beam consisting of a series of pulses of 10 ms beam-on and 90 ms beam-off. Two modules of a modified Siemens Biograph mCT PET scanner (21 × 21 cm2 each), installed 25 cm apart, were used to image the beam-induced PET activity during the beam-off periods. The modifications enable the detectors to be switched off during the beam-on periods. 12N images were reconstructed using planar tomography. Using a 1D projection of the 2D reconstructed 12N image, the activity range was obtained from a fit of the activity profile with a sigmoid function. Range shifts due to modified target configurations were assessed for multiples of the clinically relevant 108 protons per pulse (approximately equal to the highest intensity spots in the pencil beam scanning delivery of a dose of 1 Gy over a cubic 1 l volume). The standard deviation of the activity range, determined from 30 datasets obtained from three irradiations on PMMA and graphite targets, was found to be 2.5 and 2.6 mm (1σ) with 108 protons per pulse and 0.9 and 0.8 mm (1σ) with 109 protons per pulse. Analytical extrapolation of the results from this study shows that using a scanner with a solid angle coverage of 57%, with optimized detector switching and spot delivery times much smaller than the 12N half-life, an activity range measurement precision of 2.0 mm (1σ) and 1.3 mm (1σ) within 50 ms into an irradiation with 4 × 107 and 108 protons per pencil beam spot can be potentially realized. Aggregated imaging of neighboring spots or, if possible, increasing the number of protons for a few probe beam spots will enable the realization of higher precision range measurement

Radioactive Beams for Image-Guided Particle Therapy : The BARB Experiment at GSI

Several techniques are under development for image-guidance in particle therapy. Positron (β+) emission tomography (PET) is in use since many years, because accelerated ions generate positron-emitting isotopes by nuclear fragmentation in the human body. In heavy ion therapy, a major part of the PET signals is produced by β+-emitters generated via projectile fragmentation. A much higher intensity for the PET signal can be obtained using β+-radioactive beams directly for treatment. This idea has always been hampered by the low intensity of the secondary beams, produced by fragmentation of the primary, stable beams. With the intensity upgrade of the SIS-18 synchrotron and the isotopic separation with the fragment separator FRS in the FAIR-phase-0 in Darmstadt, it is now possible to reach radioactive ion beams with sufficient intensity to treat a tumor in small animals. This was the motivation of the BARB (Biomedical Applications of Radioactive ion Beams) experiment that is ongoing at GSI in Darmstadt. This paper will present the plans and instruments developed by the BARB collaboration for testing the use of radioactive beams in cancer therapy.peerReviewe